CN1674891A - Porphyrin oxygen infusion preparation for increasing oxygen concentration in tumor tissue - Google Patents

Porphyrin oxygen infusion preparation for increasing oxygen concentration in tumor tissue Download PDF

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CN1674891A
CN1674891A CNA038186160A CN03818616A CN1674891A CN 1674891 A CN1674891 A CN 1674891A CN A038186160 A CNA038186160 A CN A038186160A CN 03818616 A CN03818616 A CN 03818616A CN 1674891 A CN1674891 A CN 1674891A
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oxygen
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metal complex
porphyrin
alkylene
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土田英俊
小林纮一
小松晃之
堀之内宏久
渡边真纯
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Nipro Corp
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Abstract

A highly safe oxygen infusion for effectively increasing an oxygen partial pressure in a hypoxic region of tumor tissues, which comprises a dispersion of an albumin clathrate compound enclosing a porphyrin metal complex, dispersed in a physiologically permissible aqueous media.

Description

Improve the porphyrin oxygen therapy agent of oxygen concentration in the tumor tissues
Technical field
The present invention relates to improve the porphyrin oxygen therapy agent of oxygen concentration in the tumor tissues, it is delivered medicine to the long mammal that tumor tissues arranged to improve partial pressure of oxygen in the hypoxic position of tumor tissues.
Background technology
In vivo, endoerythrocytic hemoglobin is responsible for the oxygen transportation.Reported the research that the various synthetic compounds of many uses recover oxygen-transportation function aspect, the function of class chalybeate (II) protoporphyrin complex, it is the oxygen-binding pocket that is used for hemoglobin.For example, early stage report comprises J.P.Collman, Acc.Chem.Res., and 10,265 (1977), and F.Basolo, B.M.Hoffman, J.A.Ibers, the same, 8,384 (1975).Especially, known ferrum (II) porphyrin complex that can form the Stable Oxygen complex under the room temperature is 5,10,15,20-four (α, α, α, α-o-pivalyn-amide groups phenyl) ferrous porphyrin (II) complex (hereinafter being called " FeTpivPP complex ") (J.P.Collman etc., J.Am.Chem.Soc., 97,1427 (1975).Under the room temperature, axial alkali (as, 1-alkyl imidazole, 1-alkyl-glyoxal ethyline, or pyridine derivate) exists down, at organic solvent, as benzene, toluene, dichloromethane, N, in dinethylformamide, the oxolane etc., the FeTpivPP complex is combination or release oxygen molecule reversibly.But, if intention is used for live body with the FeTpivPP complex, artificial oxygen carrier (oxygen therapy agent) instead hemoglobin, that can demonstrate oxygen transportation function, then the FeTpivPP complex under physiological condition (promptly, in normal saline, pH7.4, temperature＜40 ℃) must have in conjunction with or discharge the ability of oxygen.The present inventor has successfully found the oxygen therapy agent, it is by effectively utilizing near the small hydrophobic environment the oxygen coordination site, with the dissolving of FeTpivPP complex in water, even also reversibly combination and release oxygen under physiological status, the dissolving of FeTpivPP complex in water can be finished by the whole bag of tricks: for example, FeTpivPP complex or its analog are embedded into (Dalton Trans., 1984 in the duplicature endoplasmic reticulum that comprises phospholipid, 1147, JP S58-21371 (A)); Seal or cover FeTpivPP complex (E.Tsuchida etc., Biochem.Biophs, Acta., 1108,253-256 (1992), JP H06-264641 (A)) with comprising the microsphere that drips the shape oil droplet; Thereby form covalent bond by inducing with amphoteric substituents and carry out self assembly (JP H06-92966 (A)); With serum albumin is enclosed in (JP H08-301873 (A)) in the hydrophobic region.And the inventor confirms, even when delivering medicine to live body, oxygen (E.Tsuchida etc., Artif.Organs Today, 5,207-215 (1996)) also can be fully transported in these oxygen therapy agent.
As mentioned above, bring into play reversible oxygen combination and releasing properties in order to make the FeTpivPP complex, must add the alkaline axial ligand of molar excess number from the outside to liquid.It has been observed by the present inventors that and do not add the system that any alkaline axial ligand just can be made stable oxygen complex, as long as will, for example alkyl imidazole derivant or alkyl histidine derivative are attached in ferrum (II) the porphyrin complex molecule as substituent group, get final product with its formation covalent bond (JP H05-85141 (A)).Some imdazole derivatives that have been widely used as axial alkali have medical character, but its major part all is highly toxic concerning bodily tissue.And if used carrier is phospholipid endoplasmic reticulum, ripido microsphere or albumin, the imdazole derivatives of excessive coexistence can become and causes the morphological characteristic factors of instability.As making the minimized approach of axial alkali addition, the present inventor does not select to have only imdazole derivatives is attached in ferrum (II) porphyrin complex.Certainly, constantly prove that by test method modification ferrum (II) porphyrin complex of gained can deliver medicine to live body (E.Tsuchida etc., Bioconjugate Chem., 11,46-50 (2000)) as oxygen carrier.
This oxygen therapy agent has extremely widely at medical field uses.The application of expection not only comprises as regenerated liquid (replacement erythrocyte) and is used for hemorrhagic shock, and as the ischemia position of oxygen carrier transportation oxygen to myocardial infarction, as the infusion liquid or the stock solution of transplantation organ, as the compensation solution of extracorporeal circulating circuit such as artificial heart and lung, as the cell of oxygen carrier transportation oxygen with the cultivation regenerating tissues.In addition, the interest that recently the oxygen therapy agent is applied to treatment of cancer reinforcing agent (that is, it resists the therapeutic properties at hypoxic position in tumor tissues) constantly increases.
Usually, cancerous cell is an anoxic cell, and the existence of anoxic cell also is one of the anti-X-ray therapy of malignant tumor or chemotherapeutic reason.Anoxic cell comprises (i) acute anoxic cell, it produces like this: the blood flow of knub position temporarily changes, it causes stopping oxygen being transported to the position that is subjected to some blood vessel control conversely, (ii) chronic anoxic cell, it produces like this: the formation of neovascularity can not be caught up with the misgrowth of tumor, causes the cell oxygen supply deficiency away from hemocyte.In fact, oxygen exists down, and tumor tissues reaches 3 times to observed increase as a result under the remolding sensitivity oxygen free condition of radiation, and the survival rate of tumor tissues also descends.When oxygen concentration is held in the palm by 0 holder-40, can obviously observe radiosensitizing effect, but change hardly when concentration exceeds this scope.
Also have many parts of not knowing in the mechanism of action of oxygen effect.For example, molecular oxygen is a strong oxidizer, and it has high electron affinity.But in simple aqueous solution, the radiosensitizing effect that is produced by oxygen does not but increase, and can not bring out oxygen effect even will think in aqueous solution that the dna molecular of target substance is exposed under the lonizing radiation at all yet.At present, it is believed that intracellular oxygen effect is to be caused by the antagonism between oxygen and the glutathion (GSH).And think that it is because born of the same parents' internal object molecule (DNA) is because directly or indirectly acting on of lonizing radiation forms free radical in the cell that cell is killed.Reduce free radical by the reaction that reduces the GSH that cell contains, and repair the destruction of lonizing radiation pair cell.If oxygen exists in a large number, then oxygen hinders GSH effect generation oxygen effect but in this case.
Up to now, also have some reports to attempt to improve anticancer character and radiated susceptibility by the oxygen concentration of using tumor tissues under the oxygen therapy agent raising hypoxia.People have noticed the effectiveness of perfluorochemical (PFC) Emulsion as the oxygen therapy agent.Nineteen eighty-two, people such as Kokuuchi have reported PFC Emulsion and chemotherapeutic combined therapy for the first time.They use the rat model of the subcutaneous transplantation cerebral tumor to study the variation (Kokuuchi etc., Cancer and chemical therapy, 11,2207-2211 (1984)) of the oxygen concentration in the brain tumor tissue that administration PFC Emulsion causes.Administration PFC Emulsion just is attended by the rising of partial pressure of oxygen in the hypoxic tissue.Based on this result, its disclosed the periphery partial pressure of oxygen remain on 300mmHg and on state under, be used in combination PFC Emulsion and chemotherapy the treatment hypoxic tissue availability.But because the low oxygen affinity of PFC, still have such problem: PFC Emulsion must be used under the hyperbaric oxygen atmosphere, for example, and under the high pressure probe.
On the other hand, Shorr etc. have proved the Oxygenation and the administration modified hemoglobin (hemoglobin (PEG-Hb) of Polyethylene Glycol (PEG)-modification of hypoxic tumor tissues, molecular weight is 128kDa) to radiotherapeutic facilitation effect (R.Linberg, C.D.Conover, K.L.Shum, R.G.S.Shorr is in the body, 12,167-174 (1998)).Four kinds of tumors, that is, osteocarcinoma, carcinoma of prostate, pulmonary carcinoma and glioma are as the object of research, and the various Homopures of administration are determined the variation of oxygen concentration in the tumor.Its demonstration, administration are after 2 hours, and PEG-Hb makes the oxygen concentration value added of hypoxic tumor tissues reach maximum (4-7 holder).Based on this fact, PEG-Hb is delivered medicine to the rat of having transplanted different radiosensible carcinoma, make its radiation of accepting gamma-radiation then, measure the size of carcinoma successively.As a result, its size that shows all tumors has all reduced.Provable from these results, PEG-Hb is effective to the Oxygenation and the radiotherapy of hypoxic tumor tissues.But known usually, the hemoglobin product is easy to go out from the blood vessel endothelium seepage, and catches around the smooth muscle that the blood vessel at approaching place loosens the factor, so it brings out vasoconstriction, and causes blood pressure to raise rapidly.
Obviously, the oxygen therapy agent is suitable for molecular oxygen is transported to the little tumor tissues of blood vessel diameter, and then it should comprise the molecule that granularity is as far as possible little.In other words, it is believed that can more effectively improve hypoxic position in the tumor tissues by artificial oxygen carrier, this artificial oxygen carrier molecule is very little, but it has certain physics chemical feature and molecular size, thereby makes it be difficult for going out from blood vessel endothelium or kidney seepage.But designing and synthesizing the oxygen therapy agent that reaches these demands, technological improvement in application and the use is people's expectation always.
Therefore, the present invention is used to overcome the problems referred to above exactly, and is intended to provide high security oxygen therapy agent by near the position administration tumor tissues, is used for effectively improving the oxygen pressure at hypoxic position in the tumor.
Summary of the invention
The present inventor, and is difficult for studying from the artificial oxygen carrier chemical compound that blood vessel endothelium or kidney seepage are gone out less than traditional oxygen carrier to diameter, and inspection, use and the administration of the oxygen therapy agent that contains the described chemical compound of high concentration are studied.The result, the present inventor finds, porphyrin metal complex is the coordinate active center of oxygen, it can be used in combination with serum albumin, to form clathrate compound or inclusion complex, wherein porphyrin metal complex is centered around in the sero-abluminous crystal structure, and gained porphyrin metal complex-albumin cage compound can be used as the preparation that oxygen efficiently can be conducted to hypoxic position in the tumor tissues.The present invention promptly is achieved by these discoveries.
According to the present invention, provide and improved the in vivo oxygen therapy agent of the interior oxygen concentration of tumor tissues, described oxygen therapy agent comprises the albumin cage compound dispersion around porphyrin metal complex, described albumin cage compound is dispersed in the water-bearing media of physiology permission.
Hereinafter with the present invention is described in detail.
The invention provides a kind of oxygen therapy agent, it comprises the albuminate around porphyrin metal complex.The oxygen therapy agent can comprise the albumin cage compound around porphyrin metal complex, and it can be dispersed in the water-bearing media of physiology permission, preferably is dispersed in normal saline solution, in the saline as phosphate-buffered.
The porphyrin metal complex that uses among the present invention is preferably the porphyrin metal complex of general formula (I) representative:
[Chem.1]
General formula (I)
Figure A0381861600091
[wherein, R 1Be chain alkylene or alicyclic hydrocarbon radical, it can have one or more substituent groups,
R 2Be the alkaline axial ligand shown in the formula (A):
[Chem.2]
Formula (A)
(wherein, R 3Be alkylene, R 4For not hindering described alkaline axial ligand and the coordinate group of central transition metal ion M), or the alkaline axial ligand of formula (B) representative:
[Chem.3]
Formula (B)
Figure A0381861600101
(wherein, R 5Be alkylene, R 6Be alkyl); With
M is the transition metal ions of the periodic table of elements the 4th or the 5th family], and/or the porphyrin metal complex of general formula (II) representative:
[Chem.4]：
General formula (II)
(wherein, R 7For hydrogen maybe can have one or more substituent chain alkylenes,
R 8Be alkoxyl, alkyl amino, or aminoacid or amino acid derivativges residue,
R 9Alkaline axial ligand for formula (C) representative:
[Chem.5]
Formula (C)
(wherein, R 10Be alkylene, R 11For not hindering described alkaline axial ligand and the coordinate group of central transition metal ion M), or the alkaline axial ligand of formula (D) representative:
[Chem.6]
Formula (D)
(R wherein 12Be alkyl) and
M is the transition metal ions of the periodic table of elements the 4th or the 5th family].
These porphyrin metal complexes constitute the coordinate active center of oxygen.
In the porphyrin metal complex of general formula (I), preferred R 1Be to have dimethylated C on the 1st 1-C 19Chain alkylene, or have substituent C on the 1st 3-C 19Alicyclic hydrocarbon radical.The example of the alicyclic hydrocarbon radical of back comprises that 1-substituted ring propyl group, 1-substituted ring amyl group, 1-substituted cyclohexyl, 1-methyl-2-cyclohexenyl group, 2-replace bornyl and 1-substituted ring adamantyl.Herein, each substituent group of above-mentioned group can be methyl, C 1-C 18Alkylamidoalkyl, C 1-C 18Alkanoyl oxygen base, or C 1-C 18Alkoxyl.
Preferred R 3Be C 1-C 10Alkylene.
Preferred R 4Be hydrogen, methyl, ethyl or propyl group.
Preferred R 5Be C 1-C 10Alkylene.
Preferred R 6Be C 1-C 18Alkyl.
In the porphyrin metal complex of general formula (II), preferred R 7Be hydrogen, vinyl, ethyl or methoxyl group.
Preferably, R 8Be C 1-C 18Alkoxyl, C 1-C 18Alkyl amino, or the residue of aminoacid or derivatives thereof.Preferably, amino acid derivativges is aminoacid-O-C 1-C 18Arrcostab.
Preferably, R 10Be C 1-C 10Alkylene.
Preferably, R 11Be hydrogen, methyl, ethyl or propyl group.
Preferably, R 12Be C 1-C 18Alkyl.
General formula (I) and (II) in M all be preferably Fe or Co.
The porphyrin metal complex of general formula (I) exists, for example, JP H06-271577 (A) and T.Komatsu etc., Chem.Lett., 2001, open among the 668-669 (2001).
The porphyrin metal complex of general formula (II) exists, for example, T.G.Traylor etc., J.Am.Chem.Soc., 101,6716-6731 (1979), open among JP S58-10388 (A) and the JP S60-17326 (A), R wherein just 8For the material of alkyl amino unexposed.R in the general formula (II) 8Be disclosing synthesizing among the embodiment that mentions below of porphyrin metal complex of alkyl amino.
As around the albuminate of porphyrin metal complex, can use serum albumin, as the human serum albumin of human serum albumin, genetic modification, bovine serum albumin etc.As albuminate, also can use the albumin of many bodily forms formula.Especially preferably use the albumin of dimerization form.Use the dimerization albumin can prevent that cage compound from oozing out blood circulation.
Comprise round the preparation of the oxygen therapy agent of the albumin cage compound of porphyrin metal complex, can use JP S08-301873 (A); E.Tsuchida etc., Bioconjugate Chem., 10,797-802 (1999); Or Bioconjugate Chem., 11, disclosed method among the 46-50 (2000).Usually wish that the contained albuminate concentration of oxygen therapy agent of the present invention is 1-30wt%, preferred, 5-25wt%.In each albuminate, the porphyrin metal chemical compound be 1-8 (mol/mol) in conjunction with number, be 0.15-36mM thereby make porphyrin metal complex concentration.The suitable dosage that the present invention cures by oxygen therapy agent is 40mL/kg body weight or this is below amount.
Oxygen therapy agent of the present invention has following excellent properties, it is necessary for tumor tissues carries out Oxidation: (i) because to account for 60% serum albumin in plasma proteins be carrier as the porphyrin metal complex at oxygen coordination activity center, therefore oxygen therapy agent of the present invention is as safe as a house and biocompatibility is very high when intravascular administration; (ii), therefore cure by oxygen therapy agent and can pass the interior little blood capillary of tumor tissues, and erythrocyte (8 μ m) can not arrive because molecular dimension can be as small as 8 * 3nm; (iii) cure by oxygen therapy agent and have low isopotential point (pI), so it can not leak out from kidney or blood vessel endothelium.
And the three dimensional structure by regulating porphyrin metal complex is the scalable oxygen affinity also, and therefore the partial pressure of oxygen according to influenced part also can efficiently transport oxygen.
Can improve the partial pressure of oxygen at hypoxic position in the tumor tissues by the mammal live body that oxygen therapy agent of the present invention is administered to the tumor tissues of having grown.
Can be by intra-arterial injection, intravenous injection, topical, be administered systemically or any other administering mode delivers medicine to live body with oxygen therapy agent of the present invention.Certainly, administration anteposition should be by oxygenate in the metal at porphyrin metal complex center.
Be to make in the hypoxic position of tumor tissues below, the follow-up explanation of the embodiment of the method that partial pressure of oxygen is improved, this method realizes by oxygen therapy agent of the present invention is delivered medicine to the mammal with tumor tissues.
By with tumor cell transplantation to laboratory animal, prepare the animal that suffers from cancer as rat, hamster, rabbit or than the hope position of Ge Er dog.Below tumor cell transplantation is gone in the right lower limb of rat to make an explanation.
Raising rat is some day until tumor growth, then under anesthesia (as, use pentobarbital sodium, ether or halothane anesthesia gas) test.Pipe was inserted the pars cervicalis tracheae of rat and made it suck oxygen by respirator under positive pressure.Polyethylene catheter is inserted in the left common carotid artery, and the distal catheter end is positioned not reach the position of common iliac artery bifurcation, carries out cannulation backward then, so that the route of administration of the sample in the row aorta to be provided down.
Can use rayed by intravenous injection phosphorescence probe (coproporphyrin palladium (PdPor)), and determine partial pressure of oxygen in the tumor tissues with the partial pressure of oxygen monitor monitors phosphorescence cancellation time.5-20 before the sample administration minute, by tail cava vein injection PdPor.Thigh is cut 20mm, normal muscle and tumor are come out, probe just is placed on above the tumor.In the test constantly process, with 37 ℃ gentle normal saline solution moistening tumor surfaces to prevent the tumor surface drying.Use partial pressure of oxygen measuring device (as, the OxySpot (trade mark) that Medical System Corp. makes), in air or contain under the atmosphere of 99% oxygen, measure 5-30 the partial pressure of oxygen of putting at right lower limb knub position place, and in contrast.Under constant voltage, carry out intra-arterial injection then with syringe pump, thus administration oxygen saturation sample (1-20mL/kg) 1-20 minute.In the time of the beginning intra-arterial injection, also the right lower limb tumor locus and the continuous variation of the partial pressure of oxygen at normal position are measured.After measure finishing,, just in time be positioned at the front of common iliac artery bifurcation, measure the size of tumor then with the conduit that is identified for the intra-arterial injection sample at otch of abdominal incision.
Under this situation, even respectively human serum albumin, bovine serum albumin and the albumin dimer of oxygen saturation normal saline, human serum albumin, genetic modification carried out intra-arterial injection, the partial pressure of oxygen of also not observing in the tumor tissues (PO2) changes.By comparison, the administration oxygen therapy agent that contains porphyrin metal complex-albumin cage compound of the present invention significantly raises the partial pressure of oxygen in the tumor tissues.It is believed that, as mentioned above, porphyrin metal complex of the present invention-albumin cage compound has small particle diameter, therefore compares with erythrocyte, the irregular blood vessel that it can more easily pass in the tumor tissues can effectively improve the partial pressure of oxygen in the tumor tissues conversely again.
The accompanying drawing summary
Fig. 1 has illustrated that the interior partial pressure of oxygen of tumor tissues that administration oxygen therapy agent of the present invention is caused changes.
Preferred forms of the present invention
To make an explanation to the present invention by embodiment below, but invention not limited.
Synthetic embodiment A: synthesize 8,13-divinyl-2-amino-carbonyl ethyl-18-(3-(1-imidazole radicals) third amino) carbonyl ethyl-3,7,12,17-tetramethyl ferrous porphyrin complex
(I) synthesize 8,13-divinyl-2-amino-carbonyl ethyl-18-(3-(1-imidazole radicals) third amino) carbonyl ethyl-3,7,12,17-tetramethyl porphyrin
With protoporphyrin IX (0.1g, 0.18mmol), (51 μ L 0.45mmol) are dosed in the three necks recovery flask of 100mL, and stirred 10 minutes for distillation pyridine (10mL) and triethylamine.Under the light shield condition, and adding (benzotriazole oxygen base) three (dimethylamino) phosphorus hexafluorophosphate in the gained mixture (124mg, 0.45mmol), stirred 10 minutes, (15 μ L, 0.14mmol), restir is 4 hours afterwards to add 1-(3-aminopropyl) imidazoles.In the gained reactant mixture, add the tetrahydrofuran solution of 5mL methylamine, and stirred 4 hours.Remove pyridine with vacuum pump decompression, fractional distillation product afterwards, and with silicagel column (chloroform/methanol/triethylamine=8/1/1) purification.Vacuum drying gained fraction.Obtain the red solid material, be 24mg (productive rate 19%) 8,13-divinyl-2-amino-carbonyl ethyl-18-(3-(1-imidazole radicals) third amino) carbonyl ethyl-3,7,12,17-tetramethyl porphyrin.
Rf:0.6 (chloroform/methanol=3/1)
IR (cm -1): ν C=0(amide groups) 1631
UV-vis/λmax(nm)(CHCl 3)：631；579；542；508；409
1H-NMR (δ (ppm)) (CDCl 3) :-4.0 (s, 2H, interior); 1.8-2.4 (m, 4H ,-C 2H 4-Im); 2.7 (m, 4H ,-CH 2-COO-,-CH 2-NH-); 3.5-3.7 (m, 15H, Por-CH 3, CONHCH 3); 4.2 (s, 4H, Por-CH 2-); 5.8 (s, 1H, Im); 6.1-6.4 (q, 4H, CH 2=CH-); 6.6 (d, 1H, Im); 8.2 (m, 2H, CH 2=CH-); 9.5-10.0 (q, 4H, meso)
FAB-MAS[m/z]：683。
(II) iron complex is synthetic
The dimethyl formamide solution of the porphyrin compound (23.9mg, 34.6 μ mol) that obtains in the 5mL said method (I) is dosed to 50mL three necks reclaims in the flask, remove wherein oxygen with 20 fens clock times with nitrogen then.In solution, add four Ferric Chloride Hydrateds (68.8mg, 346 μ mol) rapidly, under 70 ℃ blanket of nitrogen, stirred the gained mixture 3 hours.In the reaction mixture solution of chloroform dilution, add a hydrochloric acid, in the UV-visible spectrum, do not observe peak (about 450nm place), then determine to react and finish derived from bivalent cation.Use the vacuum pump removal of solvent under reduced pressure, the fractional distillation product is also used silicagel column (chloroform/methanol/triethylamine=8/1/1) purification.Through vacuum drying, obtain 7.6mg (yield 29%) brown solid material.
Rf:0.1 (chloroform/methanol/triethylamine=8/1/1)
IR (cm -1): ν C=0(amide groups): 1649
UV-vis/λmax(nm)(CHCl 3)：583；531；406
FAB-MAS[m/z]：736。
Synthetic Embodiment B: synthesize 8,13-divinyl-2-dodecyl amino carbonyl ethyl-18-(methyl-O-histidine) carbonyl ethyl-3,7,12,17-tetramethyl ferrous porphyrin complex
Remove and use histidine-O-methyl ester to replace 1-(3-aminopropyl) imidazoles, use lauryl amine to replace outside the methylamine, make 8 according to the mode identical with method (I) in the synthetic embodiment A, 13-divinyl-2-dodecyl amino carbonyl ethyl-18-(methyl-O-histidine) carbonyl ethyl-3,7,12,17-tetramethyl porphyrin closes ferrum, and yield is 25%.
Rf:0.4 (chloroform/methanol=15/1)
IR (cm-1): ν C=O(amide groups): 1640
UV-vis/λmax(nm)(CHCl 3)：631；575；540；409
1H-NMR (δ (ppm)) (CDCl 3) :-4.0 (s, 2H, interior); 0.8 (s, 3H ,-(CH 2) 10CH 3); 1.2-1.8 (m, 20H ,-CH 2-); 1.9 (t, 4H ,-CH 2(C=O) NH-); 3.2 (s, 2H ,-Im-CH 2-); 3.3 (t, 2H ,-(C=O) NHCH 2-); 3.5-3.7 (m, 12H, Por-CH 3); 3.7 (m, 3H, His-OMe); 4.2 (s, 4H, Por-CH 2-); 4.8 (s, 1H, His-CH 2CH-); 6.1-6.4 (q, 4H, CH 2=CH-); 6.8 (s, 1H, Im); 7.6 (s, 1H, Im); 8.2 (m, 2H, CH 2=CH-); 9.5-10.0 (q, 4H, meso)
FAB-MAS[m/z]：881
Use the gained porphyrin, prepare its iron complex according to the mode identical with method (II) in the synthetic embodiment A.
[embodiment 1]
Prepare oxygen therapy agent of the present invention
Reinforced 10mL (2.5mg, 37.5 μ mol) human serum albumin (25wt%) and 1L phosphate buffered saline (PBS) (pH8.1) are loaded onto the 500mL Dropping funnel then in separable flask (2L).In addition; reinforced 250mL 2-8-(2-methyl isophthalic acid-imidazole radicals) decoyl oxygen ylmethyl-5 in reclaiming flask (300mL); 10,15,20-four-(α; α; α, α-o-valeryl amido phenyl) ferrous porphyrin (II) complex (hereinafter is called " FepivP (Im) ", 390mg; 300 μ mol) alcoholic solution, and couple together by polytetrafluoroethylene (trade mark) pipe and above-mentioned separable flask.Keep this Guan Buyu liquid surface contact.In the recovery flask that contains FepivP (Im) alcoholic solution, blast carbon monoxide, expellant gas is flowed in the albumin solution.Meanwhile, proceed to blast in order to avoid albumin solution spumes.Bubbling and exhaust stream were operated about 60 minutes.Under carbon monoxide atmosphere, in FepivP (Im) alcoholic solution, add 250 μ L aqueous ascorbic acids (0.6M), and stirred 5 minutes.In this way, the haemachrome reduction forms carbon monoxide complexes, and solution colour becomes dark red.
The alcoholic solution of gained carbon monoxide FepivP (Im) complex is transferred in the Dropping funnel on the separable flask, and slowly drops in the albumin solution.After dripping end, agitating solution 30 minutes.
Next with aluminium foil light is shielded, and carry out following step with this understanding.Use has the closed circuit type ultrafilter of ultrafilter membrane, and (Pellicon 2 MINI HOLDER (trade name), Cat.NO.XX42PMINI), the filter area of ultrafilter membrane is 0.1m 2, molecular weight is by 10kDa, and P2B010A01 (trade name of MILIPORE) filters 20% alcoholic solution of 1.25L gained albumin-haemachrome.When filtering out the 50mL filter liquor, and adding 50mL phosphate buffer (1mM, pH7.3).Repeat this step until filtering out 10L (1.25 * 8L) phosphate buffered solution.Then, albumin-haemachrome solution is concentrated into 100mL and being collected in the container.
Filter gained concentrated solution (about 200mL) with filter (DISMIC (trade name), 0.45 μ m), and, obtain about 50mL concentrated solution with ultra-filtration unit (UHP-76K, ADVANTEC (trade mark)) concentrating filtrate.
In the gained concentrated solution, add the sodium chloride solution of 20wt%, make sodium chloride concentration become 140mM.
Use pH analyzer and salinometer to measure the pH and the Na of albumin-haemachrome solution +Concentration.Determine albumin concentration by bromocresol green (BCG) test, determine FepivP (Im) concentration by ICP (inductively coupled plasma) emission spectrometric method.
Albumin-haemachrome (carbon monoxide complexes) solution (20mL) is dosed to 100mL reclaims in the flask, and be connected with Rotary Evaporators.Reclaim flask with ice-water bath cooling, flask was reclaimed in rotation simultaneously, and made the upper piston of oxygen flow supercooling pipe with 20 fens clock times.Then, Halogen light (500w) is fixed on rotation reclaims on the position at 15-20cm place above the flask, and shone albumin-haemachrome solution 10 minutes.Uv-vis spectra by albumin-haemachrome solution absorbs and λ max can determine the formation of oxygen complex.The molar extinction coefficient of gained oxygen complex (ε 426) about 1.16 * 10 5M -1Cm -1
The mensuration of partial pressure of oxygen in healthy cell and the tumor cell
Use Donryu rat (Crj-Donryu; Nippon Charles River, male, weight: about 200g, 6 weeks are big) as experimental animal, by biological cleaning system, under the condition of ad lib pill and water, it is raised.By the transplanting of going down to posterity in the abdomen, make the tumor cell of transplanting, ascites hepatocarcinoma LY80 growth.In order to obtain to suffer from the rat of cancer, made growth of tumour cell after the transplanting 7 days.Cut at the right lower limb of rat before transplanting 8 days, and with the syringe of 27G and 1mL with 5 * 10 6Individual cell is implanted in below the leg muscle just.Intravenous injection coproporphyrin palladium (PdPor), carry out light radiation then, use afterwards partial pressure of oxygen measure system (Oxyspot Photomeric oxygenation measurement system (OxySpot, Medical SystemCorp.) monitoring, thus determine partial pressure of oxygen in the tumor tissues by the phosphorescence cancellation time.Before the sample administration 15 minutes, use the 24G remaining needle by tail cava vein injection PdPor.On thigh, cut the little otch of 20mm, normal muscle and tumor are all come out, measuring probe just is placed on 5mm distance above the tumor.In the measuring process with 37 ℃ gentle normal saline rinsing tumor surface to prevent the tumor surface drying.
With ether inhalant anesthetized rat, through pars cervicalis tracheae with 14G-Angiocath (trade mark) intubate, by artificial respirator (artificial respirator model SN 480-7, Shinano MFG., the CO.Ltd manufacturing) (80 times/minute) make it absorb oxygen under positive pressure, simultaneously by the supply of meiofauna anesthetic machine and air or the blended 1% halothane anesthesia gas of oxygen (FiO2,1% Hal Fluothane).With polyethylene catheter (SP10, single chamber, internal diameter: 0.28mm, external diameter: 0.61mm) insert in the left common carotid artery, and be fixed on apart from the position of common iliac artery bifurcation (about 9.5cm) 1cm, carry out cannulation backward then, so that the route of administration of the sample in the row aorta to be provided down.
Peel off after the right lower limb tumor cell skin, by the tail vein injection PdPor (0.24cc (10mg/mL, 0.9mL/kg)) of rat tails.Use OxySpot (trade mark), in air or contain under the atmosphere of 99% oxygen, measure the partial pressure of oxygen of 20 points at right lower limb knub position place, and in contrast.Under constant voltage, continue intra-arterial injection 4 minutes (2.5mL/kg/ minute) then with syringe pump (FP-W-100, Matys, ToyoSangyo Ltd.), thus the oxygen-saturated sample of administration (10mL/kg).In the time of the beginning intra-arterial injection, also measure the partial pressure of oxygen of tumor locus and normal position (5 points continue 15 minutes), to determine the continuous variation of partial pressure of oxygen.After measuring end,, be positioned at the position that does not reach the common iliac artery crotch, and measure the size of tumor with the intra-arterial injection conduit of determining sample at otch of abdominal incision.
Under 99% oxygen atmosphere, normal position of right lower limb and tumor locus partial pressure of oxygen (PO 2) be respectively 14-16 holder and 1.4-1.7 holder, as shown in table 1.Compare with the dividing potential drop at normal position, the dividing potential drop of tumor locus significantly reduces.Therefore, can be sure of only to pass through the increase of the oxygen concentration of rats breathing, the partial pressure of oxygen of tumor locus can not increase.
The initial value of the various parameters of r human serum albumin-haemachrome processing (rHSA-Heme) group (4 rats) and r human serum albumin (rHSA) processing group (4 rats) is as shown in table 1.
[table 1]
The group that rHSA-Heme handles The group that RHSA handles
Weight (g) ????213±4.2 ????203±6.3
Tumor size (mm) ????16.5×14.0 ????19.0×14.0
PO 2(holder) (tumor cell) ????1.4±0.2 ????1.7±0.2
PO 2(holder) (tumor cell) ????15.7±2.3 ????14.8±2.8
Blood gas parameter: pH PO 2(holder) PCO 2(holder) ? ????7.41±0.04 ????394±73 ????34.6±4.2 ? ????7.42±0.04 ????402±60 ????33.0±2.8
Next, the human serum albumin (rHSA) of, genetic modification oxygen-saturated, but partial pressure of oxygen (PO by the intra-arterial injection administration 2) do not change.Comparatively speaking, during with the oxygen therapy agent product administration of the present invention for preparing above, the partial pressure of oxygen in the tumor tissues rises to up to 3.5 holders.The result as shown in Figure 1.Behind the administration oxygen therapy agent of the present invention product, partial pressure of oxygen is 2.5 times before the administration.Can think can effectively raise partial pressure of oxygen in the tumor tissues of porphyrin metal complex of the present invention-cage type albuminate, its reason is: because that itself and erythrocyte are compared molecular dimension is littler, so this chemical compound can easily pass the irregular blood vessel in the tumor tissues.
[embodiment 2]
Remove and use 2-8-(1-imidazole radicals) decoyl oxygen ylmethyl-5; 10; 15; 20-four-(α; α; α, α-o-(1-methyl cyclohexane acyl group) aminophenyl) ferrous porphyrin (II) complex replaces outside the FepivP (Im) among the embodiment 1, measures the effect of oxygen supply to hypoxic position in the tumor tissues according to the mode identical with embodiment 1.Partial pressure of oxygen in the tumor tissues is increased to up to about 7.0 holders.Therefore, it shows the effect of organizing oxygen supply to produce to hypoxic tumors by administration albumin-haemachrome (it is artificial oxygen carrier).
[embodiment 3]
Remove and use 8,13-divinyl-2-methoxycarbonyl ethyl-18-(3-(1-imidazole radicals) propyl group amino) carbonyl ethyl-3,7,12,17-tetramethyl ferrous porphyrin (II) complex replaces outside the FepivP (Im) among the embodiment 1, measures the effect of oxygen supply to hypoxic position in the tumor tissues according to the mode identical with embodiment 1.Partial pressure of oxygen in the tumor tissues is increased to about 1.6 holders.Therefore, it shows the effect of organizing oxygen supply to produce to hypoxic tumors by administration albumin-haemachrome (it is artificial oxygen carrier).
Industrial applicibility
As mentioned above, according to the present invention, it provides a kind of very safe oxygen therapy agent product, when it is delivered medicine near the tumor tissues position, and the partial pressure of oxygen at hypoxic position in the tumor tissues that can effectively raise.

Claims (4)

1. improve the in vivo oxygen therapy agent of tumor tissues oxygen concentration, described oxygen therapy agent comprises albumin cage compound dispersion, and this dispersion comprises porphyrin metal complex, and it is dispersed in the water-bearing media of physiology permission.
2. according to the oxygen therapy agent of claim 1, wherein said porphyrin metal complex is the porphyrin metal complex of general formula (I) representative:
[Chem.7]
General formula (I)
[wherein, R 1Be chain alkylene or alicyclic hydrocarbon radical, it can have one or more substituent groups,
R 2Be the alkaline axial ligand shown in the formula (A):
[Chem.8]
Formula (A)
Figure A038186160002C2
(wherein, R 3Be alkylene, R 4For not hindering described alkaline axial ligand and the coordinate group of central transition metal ion M), or the alkaline axial ligand of formula (B) representative:
[Chem.9]
Formula (B)
(wherein, R 5Be alkylene, R 6Be alkyl); With
M is the transition metal ions of the periodic table of elements the 4th or the 5th family], and/or the porphyrin metal complex of general formula (II) representative:
[Chem.10]：
General formula (II)
Figure A038186160003C2
(wherein, R 7For can having one or more substituent chain alkylenes or alicyclic hydrocarbon radical,
R 8Be alkoxyl, alkyl amino, amino or amino acid derivativges residue,
R 9Alkaline axial ligand for formula (C) representative:
[Chem.11]
Formula (C)
Figure A038186160004C1
(wherein, R 10Be alkylene, R 11For not hindering described alkaline axial ligand and the coordinate group of central transition metal ion M), or the alkaline axial ligand of formula (D) representative:
[Chem.12]
Formula (D)
(R wherein 12Be alkyl) and
M is the transition metal ions of the periodic table of elements the 4th or the 5th family].
3. according to the oxygen therapy agent of claim 2, wherein said porphyrin metal complex is the porphyrin metal complex of general formula (I), wherein R 1Be to have dimethylated C on the 1st 1-C 19Chain alkylene, or have substituent C on the 1st 3-C 19Alicyclic hydrocarbon radical, R 3Be C 1-C 10Alkylene, R 4Be hydrogen, methyl, ethyl or propyl group, R 5Be C 1-C 10Alkylene, R 6Be C 1-C 18Alkyl, M are Fe or Co.
4. according to the oxygen therapy agent of claim 2, wherein said porphyrin metal complex is the porphyrin metal complex of general formula (II), wherein R 7Be hydrogen, vinyl, ethyl or methoxyl group; R 8Be C 1-C 18Alkoxyl, C 1-C 18The residue of alkyl amino, aminoacid or derivatives thereof; R 10Be C 1-C 10Alkylene; R 11Be hydrogen, methyl, ethyl or propyl group; R 12Be C 1-C 18Alkyl; And M is Fe or Co.
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